Process for producing optically active ester

a technology of optically active and ester, which is applied in the preparation of carboxylic acid esters, chemistry apparatus and processes, and organic chemistry, etc. it can solve the problems of not being considered an industrially applicable process, not being suited to the production of high-optical purity 2-hydroxybutyric, and being very expensive products. , to achieve the effect of high yield and high optical yield

Inactive Publication Date: 2009-05-07
KOWA CO LTD
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AI Technical Summary

Benefits of technology

[0016]According to the process of the present invention, an optically active 2-hydroxybutyric ester, which is a useful material for producing pharmaceuticals, pesticides, and industrial products, can be produced in high yield and high optical yield.
[0017]The reaction steps included in the production process of the present invention will now be described.
[0018]In Step 1, an optically active 2,3-epoxybutyric ester (2) is reacted with a thiol R1—SH (wherein R1 has the same meaning as defined above) in the presence of scandium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate, to thereby produce an optically active 3-alkylthio-2-hydroxybutyric ester or an optically active 2-hydroxy-3-phenylthiobutyri

Problems solved by technology

These optically active 2-hydroxybutyric esters are commercially available reagents (Aldrich), but are very expensive products.
Thus, the process 1) is not suited for the production of high-optical purity 2-hydroxybutyric ester and is not considered an industrially applicable process.
In addition, a 2-ketobutyric ester is chemically unstable (Non-Patent Document 1) and very expensive, which is problematic.
However, three steps are required for the target product, resulting in low overall yield, and a large amount of solvent is required for reaction and post treatment.
Thus, the process 2) has problematically poor efficiency in terms of production conditions.
In addition, since the process 2) includes a step of forming an unstable diazonium salt, reaction conditions are difficult to control, leading to variation in yield and optical purity of the target product.
However, the 2-acyloxyacryl

Method used

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  • Process for producing optically active ester
  • Process for producing optically active ester
  • Process for producing optically active ester

Examples

Experimental program
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Effect test

example 1

Synthesis of n-butyl(S)-2-hydroxy-(S)-3-phenylthiobutyrate

[0043]Scandium trifluoromethanesulfonate [Sc(OTf)3] (311 mg) and thiophenol (0.064 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (100 mg, 97.3% ee) (product of Osaka Organic Chemical Industry, Ltd.) in methylene chloride (5.0 mL), and the mixture was stirred at the same temperature for 10 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane / ethyl acetate=5 / 1), to thereby yield colorless oil (117 mg, 95.3%).

[0044]IR(ATR); 3484, 2961, 2933, 2873, 1732, 1645, 1474, 1439, 1380, 1240, 1211, 1129, 1090, 1051, 1024, 951, 747, 692 cm−1.

[0045]1H-NMR (400 MHz, CDCl3) δ; 0.94 (t, J=7 Hz, 3H), 1.27 (d, J=7 Hz, 3H) 1.38 (sext...

example 2

Synthesis of n-butyl(S)-2-hydroxy-(S)-3-phenylthiobutyrate

[0048]Ytterbium trifluoromethanesulfonate [Yb(OTf)3] (196 mg) and thiophenol (0.032 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (50 mg) in methylene chloride (3.0 mL), and the mixture was stirred at the same temperature for 24 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through preparative thin-layer chromatography (n-hexane / ethyl acetate=5 / 1), to thereby yield colorless oil (69 mg, 81.3%).

example 3

Synthesis of n-butyl(S)-2-hydroxy-(S)-3-ethylthiobutyrate

[0049]Scandium trifluoromethanesulfonate [Sc(OTf)3] (311 mg) and ethanethiol (0.047 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (100 mg) in methylene chloride (5.0 mL), and the mixture was stirred at the same temperature for 7 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane / ethyl acetate=5 / 1), to thereby yield colorless oil (116 mg, 83.4%).

[0050]IR(ATR); 3490, 2962, 2931, 2873, 1732, 1456, 1379, 1260, 1239, 1209, 1130, 1088, 1060, 980, 784, 766, 738, 699 cm−1.

[0051]1H-NMR (400 MHz, CDCl3) δ; 0.95 (t, J=7 Hz, 3H), 1.24 (d, J=7 Hz, 3H), 1.28 (t, J=7 Hz, 3H), 1.40 (sext, J=7 Hz, 2H), 1.63-1.70 (m, 2H), 2.57-2....

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Abstract

A process for producing an optically active 2-hydroxybutyric ester (1), characterized by including reacting an optically active 2,3-epoxybutyric ester (2) with a thiol in the presence of scandium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate, to thereby produce Compound (3), and subjecting Compound (3) to desulfurization reaction:
(wherein R represents a C1 to C6 alkyl group or a C7 or C8 aralkyl group; R1 represents a C1 to C12 alkyl group or a phenyl group; and * represents S- or R-absolute configuration).
The present invention provides a process for producing an optically active 2-hydroxybutyric ester at high yield and high optical purity.

Description

TECHNICAL FIELD[0001]The present invention relates to a process for producing an optically active 2-hydroxybutyric ester, which is a useful material for producing pharmaceuticals, pesticides, and industrial products.BACKGROUND ART[0002]Optically active 2-hydroxybutyric esters are compounds useful as a reagent or a starting material for producing pharmaceuticals, pesticides, and industrial products. For example, these esters serve as an important starting material for producing (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, which is a PPARα-selective activating agent and serves as a useful prophylactic and / or therapeutic agent for hyperlipemia, arteriosclerosis, diabetes, diabetes complications, inflammation, heart diseases, etc., and is represented by the following formula (A):(Patent Document 1).[0003]These optically active 2-hydroxybutyric esters are commercially available reagents (Aldrich), but are very expensive products. Hitherto,...

Claims

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Application Information

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IPC IPC(8): C07C69/66
CPCC07B53/00C07B2200/07C07C67/317C07C319/14C07C69/675C07C323/52
Inventor ARAKI, TAKAAKIYAMAZAKI, YUKIYOSHISHIBUYA, KIMIYUKI
Owner KOWA CO LTD
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